1. Field of the Invention
The present invention is directed to an injectable formulation of nanoparticulate naproxen that produces minimal or no intramuscular pain or burning sensation upon administration, methods of making such a formulation, and methods of using such a formulation.
2. Description of the Related Art
Naproxen, also known as 6-methoxy-.alpha.-methyl-2-napthalene-acetic acid and d-2(6-methoxy-2-naphthyl)propionic acid, is a well-known anti-inflammatory, analgesic, and antipyretic agent. It has been approved in many countries around the world for almost two decades and has a very safe risk-benefit profile. It is sold under the trade names ALEVE.RTM., ANAPROX.RTM., NAPROSYN.RTM., and SYNFLEX.RTM. (all available from Syntex Chemicals, Inc.). See The Merck Index, 10.sup.th Edition, pp. 6274 (Merck & Co., Rahway, N.J., 1983).
Naproxen, which is highly water insoluble, i.e., less than 10 mg/ml, has the following chemical structure: ##STR1##
Naproxen is a non-steroidal anti-inflammatory drug (NSAID) often used to relieve the inflammation, swelling, stiffness, and joint pain associated with rheumatoid arthritis, osteoarthritis (the most common form of arthritis), juvenile arthritis, ankylosing spondylitis (spinal arthritis), tendinitis, bursitis, and acute gout. In addition, it is used to treat pain associated with menstrual periods, migraine headaches, and other types of mild to moderate pain.
Naproxen acts by suppressing the production of prostaglandins, which are hormone-like substances that act on local tissues to produce pain and inflammation. Its pharmaceutical forms of delivery include tablets, capsules, and liquids. Delivery characteristics and forms are disclosed in, for example, U.S. Pat. Nos. 3,904,682; 4,009,197; 4,780,320; 4,888,178; 4,919,939; 4,940,588; 4,952,402; 5,200,193; 5,354,556; 5,462,747; and 5,480,650, all of which are specifically incorporated by reference. The synthesis of naproxen is described in U.S. Pat. Nos. 3,904,682 and 4,009,197.
Naproxen is a more potent pain reliever than aspirin, especially for menstrual cramps, toothaches, minor arthritis, and injuries accompanied by inflammation, such as tendinitis. The naproxen sodium salt is specifically indicated in the treatment of various types of acute and very high intensity pain because it induces a rapid and sustained remission. In addition, it is possible to obtain a good analgesic effect with few administrations, due to naproxen's particular pharmacokinetics. Tablet formulations of naproxen were approved for OTC ("over the counter" as compared to prescription) marketing by the U.S. Food and Drug Administration in 1994.
Because of naproxen's low solubility, it is generally formulated for oral administration. However, oral administration of naproxen frequently results in gastrointestinal irritation. All NSAIDs produce gastrointestinal symptoms to some degree upon oral administration. Such symptoms most commonly are constipation, gastric burns, diarrhea, stomatitis, dyspepsia, nausea, vomiting, upper abdominal pain, and heartburn. Oral administration may also lead to an ulcer or bleeding from the stomach or duodenum.
Gastrointestinal irritation resulting from oral administration of an NSAID can be significant. Numerous literature articles detail the severity of gastric irritation caused by NSAID compositions. For example, one report states that between 10,000 and 20,000 people in Canada each year are hospitalized with major gastro-intestinal bleeding caused by oral ingestion of NSAIDs, with effects resulting in death for at least 1,000 of these patients. See Marketplace, Oct. 24, 1996. Yet another reference states that gastrointestinal complications of NSAID use may be responsible for over 10,000 deaths each year. See American Family Physician, March 1997.
Injectable formulations of naproxen are preferable over oral administration forms for several reasons. First, such formulations can lessen or eliminate side effects of gastro-intestinal irritation. Second, intravenous (IV) or intramuscular (IM) administration of a drug results in a significantly shorter response time as compared to oral administration. Moreover, injectable formulations of pain medication are also preferable for post-operative health care, where oral administration may not be feasible. Injectable formulations of naproxen are particularly preferred, as naproxen is not addictive, in contrast to other injectable formulations of drugs, such as morphine and ketorolac (Toradol.RTM.).
Injectable formulations of naproxen have been used prior to the present invention. See Marsala et al., "Treatment of Acute Pain of Ureteral and Biliary Colic with Naproxen Sodium Administered by the Parenteral Route," Int. J. Clin. Pharmacol. Res., 6:495-500 (1986) (IM and IV injections of naproxen); L. Kvarnes, "Naproxen Sodium Versus Pentazocine in Treating Postoperative Pain," Curr. Ther. Res., Clin. Exp., 46:259-268 (1989) (IM injections of naproxen). However, injectable naproxen formulations arc difficult to formulate due to the low solubility of naproxen. Moreover, current injectable formulations of naproxen are undesirable because they produce intense pain and/or a burning sensation upon administration. Such pain is counter-productive, particularly as the patient to be treated is generally already suffering from intense pain. Thus, the pain upon administration interferes with patient treatment, and has led to the use of alternative, but less desirable, injectable pain medications.
There is currently a need for a safe and effective injectable formulation of naproxen that produces minimal or no pain or burning sensation upon administration. In addition, there is a need in the art for methods of making and methods of using such naproxen formulations. The present invention satisfies these needs.